Poly ADP ribose polymerase inhibitors (PARPi) have shown extraordinary clinical benefits in the treatment of BRCA mutant homologous recombination (HR) deficient ovarian cancer. A critical clinical problem is chemotherapy drugs, including PARPi, are far less effective in BRCA wild-type HR proficient, poor prognostic ovarian cancer (e.g. CCNE1 amplification/gain). Combining PARPi with other drugs is an emerging strategy to overcome this problem. The PI has shown epigenetic drugs, histone deacetylase inhibitors (HDACi), bromodomain extra-terminal inhibitors (BETi), and DNA methyltransferase inhibitors (DNMTi), enhance PARPi efficacy in preclinical models of HR proficient ovarian cancer. Epigenetic drugs primarily activate or repress gene transcription in a cell type- and context-dependent manner. In the context of CCNE1 amplified/gain HR proficient ovarian cancer, the PI has demonstrated chemically diverse epigenetic drugs induce a ?BRCA mutant-like? contextual synthetic lethal phenotype, characterized by repressed HR gene expression and function. The overall objective of this proposal is to determine if the extraordinary benefits of PARPi therapy can be extended through rational PARPi-epigenetic drug combinations for a new indication in BRCA wild-type HR proficient, poor prognostic ovarian cancer. Even with extensive published and preliminary results from the PI's group and others, gaps in knowledge remain regarding optimal PARPi-epigenetic regimens for clinical use, appropriate biomarkers of response, and precise underlying mechanisms of action. To address these gaps, we will apply a translational research approach that takes full advantage of our collective expertise including: unique primary cell lines and patient-derived xenograft (PDX) preclinical models, clinical patient biosamples associated with an approved phase 1/2 trial, and state-of-the-art genome-wide strategies. As a result, we are perfectly positioned to test the central hypothesis that epigenetic drugs enhance PARPi efficacy in BRCA wild-type HR proficient ovarian cancer by inducing a BRCA mutant-like phenotype through repression of common HR transcriptional targets and contextual synthetic lethality. The Specific Aims are designed to determine the therapeutic potential of new PARPi-epigenetic drug regimens in preclinical models of ovarian cancer, to investigate HR deficient status as a surrogate biomarker of a new PARPi-epigenetic drug regimen in clinical development, and to elucidate mechanisms of response to PARPi-epigenetic drug regimens in HR proficient ovarian cancer cells using genome-wide strategies. This innovative translational approach has high potential for advancing new preclinical PARPi-epigenetic drug regimens to the clinic, along with new biomarkers as companion diagnostics, and new mechanistic insights for both PARPi and epigenetic drugs. As a result, the proposed studies will have broad implications beyond ovarian cancer. Because a critical clinical problem is the lack of effective treatment options for BRCA wild-type HR proficient tumors, establishing benefits of PARPi-epigenetic therapy for this typically poor prognostic ovarian cancer has the potential for high impact.